Scalable and sustainable electrochemical allylic C-H oxidation

Abstract

New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as "classics". Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.

Fig. 1. Widely applied allylic oxidation

a, Sustainable allylic C–H oxidation is an unsolved problem. b, Case studies from classic total syntheses. c, Electrochemical oxidation represents a potential solution.

Fig. 2

Optimization of a new sustainable allylic C–H oxidation.

Fig. 3. Scope of the electrochemical allylic oxidation

Yields refer to isolated yields of products after chromatography on SiO₂. ^aStandard conditions: terpenoid substrate (0.5 mmol), Cl₄NHPI (0.1 mmol), pyridine (1.0 mmol), ^tBuOOH (0.75 mmol), LiClO₄ (0.3 mmol), and acetone (3 mL). ^bMeCN (3 mL) replaced acetone as solvent. ^cterpenoid substrate (0.25 mmol), Cl₄NHPI (0.1 mmol), pyridine (1.0 mmol), LiClO₄ (0.3 mmol), CH₂Cl₂ (1.5 mL), and acetone (1.5 mL) were used. ^dSee Supporting Information for references.

Fig. 4. Practicality of electrochemical method

a. 100-gram scale electrochemical allylic oxidation. b. Calculated Process Greenness Score (PGS) for CrO₃-mediated, RuCl₃-catalyzed, and electrochemical oxidation of deoxy-36 to 36 shows improvement from 32.1% to 55.8%. Cost and toxicity associated with chromium and ruthenium use and disposal are not included in PGS. c. Use of 6-volt lantern battery as readily-available power source for allylic oxidation.

Fig. 5

Proposed mechanism for electrochemical allylic oxidation.